Paroxetine-Derived Compounds Show Promise Against Parasite Purine Enzyme

A new series of carbothioamide derivatives of paroxetine has shown measurable inhibitory activity against hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRT), a central enzyme of the purine salvage pathway in protozoan parasites including Plasmodium. Because these parasites are purine auxotrophs that depend on scavenging purines to build their nucleic acids, blocking this salvage route offers a way to starve the pathogen of essential DNA and RNA building blocks. The study identified seventeen candidate inhibitors as potential starting points for anti-parasitic drug development.

The compounds were prepared through a single-step chemical transformation in which paroxetine was reacted with a series of substituted phenyl isothiocyanates. All seventeen derivatives were purified and their structures confirmed using mass spectrometry, FT-IR, UV spectroscopy, and proton and carbon-13 NMR.

When tested in an in vitro UV-based spectrophotometric assay, every compound inhibited HGXPRT, with IC50 values ranging from 19.0 to 76.9 µM. The most active analogue, compound 13, achieved an IC50 of 19.0 ± 2.09 µM, though this remained less potent than the reference inhibitor 9-deazaguanine, which recorded 12.00 ± 1.0 µM in the same assay.

To understand how the compounds engage the enzyme, the team carried out biophysical measurements, molecular docking and molecular dynamics simulations. These analyses suggested that the derivatives bind not at the catalytic center but at a putative allosteric site of the enzyme.

The simulations were used to assess the stability of the predicted enzyme-inhibitor complexes, complementing the docking and biophysical data on how the inhibitors interact with HGXPRT.

Safety profiling formed the final layer of the evaluation. In silico ADMET analysis and an in vitro MTT cytotoxicity assay indicated that the compounds are largely non-cytotoxic, an encouraging early signal for a series intended for further optimization.

The authors position these molecules as hit compounds against HGXPRT that warrant continued investigation as potential anti-parasitic drug leads. Because the work is at the biochemical and computational stage, with enzyme inhibition measured in vitro rather than in infected animals or patients, the findings mark an early but concrete step in the search for new antiparasitic candidates.

Overall, the study demonstrates that a chemically accessible paroxetine scaffold, modified with simple one-step chemistry, can yield compounds that interfere with a metabolic pathway that protozoan parasites rely on, while showing largely non-cytotoxic profiles in the assays performed so far.

Subject of Research: HGXPRT-targeted carbothioamide paroxetine analogues as potential antiparasitic inhibitors

Article Title: Carbothioamide functionalized paroxetine analogues as antiparasitic agents targeting the hypoxanthine-guanine-xanthine phosphoribosyltransferase enzyme: Synthesis, characterization, biochemical, biophysical, and in silico studies

Article References: Hammal, L., Ali, M., Zafar, N., Mari, S. H., Zafar, H., Wahab, A.-T., Siddiqui, H., Javaid, S., & Choudhary, M. I. (2026). Carbothioamide functionalized paroxetine analogues as antiparasitic agents targeting the hypoxanthine-guanine-xanthine phosphoribosyltransferase enzyme: Synthesis, characterization, biochemical, biophysical, and in silico studies. PLOS One, 21(10), e0359519. https://doi.org/10.1371/journal.pone.0359519

Image Credits: AI Generated

DOI: 10.1371/journal.pone.0359519

Keywords: HGXPRT, paroxetine analogues, carbothioamides, purine salvage pathway, antiparasitic agents, enzyme inhibition, molecular docking, ADMET, cytotoxicity, Plasmodium, Carbothioamide, functionalized